KRAS, a small GTPase involved in cell proliferation and differentiation, frequently gains activating mutations in human cancers. For KRAS to function, it must bind the plasma membrane (PM) via interactions between its membrane anchor and phosphatidylserine (PtdSer). Therefore, depleting PM PtdSer abrogates KRAS PM binding and activity. From a genome-wide siRNA screen to identify genes regulating KRAS PM localization, we identified a set of phosphatidylinositol (PI) 3-phosphatases: myotubularin-related proteins (MTMR) 2, 3, 4, and 7. Here, we show that silencing MTMR 2/3/4/7 disrupts KRAS PM interactions by reducing PM PI 4-phosphate (PI4P) levels, thereby disrupting the localization and operation of ORP5, a lipid transfer protein maintaining PM PtdSer enrichment. Concomitantly, silencing MTMR 2/3/4/7 elevates PM PI3P levels while reducing PM and total PtdSer levels. We also observed MTMR 2/3/4/7 expression is interdependent. We propose that the PI 3-phosphatase activity of MTMR is required for generating PM PI, necessary for PM PI4P synthesis, promoting the PM localization of PtdSer and KRAS.
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May 02 2025
MTMR regulates KRAS function by controlling plasma membrane levels of phospholipids
Taylor E. Lange
,
Taylor E. Lange
(Conceptualization, Formal analysis, Investigation, Writing - review & editing)
1Department of Biochemistry and Molecular Biology,
Boonshoft School of Medicine, Wright State University
, Dayton, OH, USA
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Ali Naji
,
Ali Naji
(Investigation)
2Department of Diagnostic and Biomedical Sciences,
School of Dentistry, The University of Texas Health Science Center at Houston
, Houston, TX, USA
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Ransome van der Hoeven
,
Ransome van der Hoeven
(Investigation, Methodology, Resources, Validation, Writing - review & editing)
2Department of Diagnostic and Biomedical Sciences,
School of Dentistry, The University of Texas Health Science Center at Houston
, Houston, TX, USA
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Hong Liang
,
Hong Liang
(Investigation)
3Department of Integrative Biology and Pharmacology,
McGovern Medical School, University of Texas Health Science Center
, Houston, TX, USA
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Yong Zhou
,
Yong Zhou
(Data curation, Formal analysis, Investigation, Validation)
3Department of Integrative Biology and Pharmacology,
McGovern Medical School, University of Texas Health Science Center
, Houston, TX, USA
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Gerald R.V. Hammond
,
Gerald R.V. Hammond
(Methodology, Writing - review & editing)
4Department of Cell Biology,
University of Pittsburgh School of Medicine
, Pittsburgh, PA, USA
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John F. Hancock
,
John F. Hancock
(Conceptualization, Funding acquisition, Project administration, Writing - review & editing)
3Department of Integrative Biology and Pharmacology,
McGovern Medical School, University of Texas Health Science Center
, Houston, TX, USA
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Kwang-jin Cho
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing)
1Department of Biochemistry and Molecular Biology,
Boonshoft School of Medicine, Wright State University
, Dayton, OH, USA
Correspondence to Kwang-jin Cho: [email protected]
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Taylor E. Lange
Conceptualization, Formal analysis, Investigation, Writing - review & editing
1Department of Biochemistry and Molecular Biology,
Boonshoft School of Medicine, Wright State University
, Dayton, OH, USA
Ali Naji
Investigation
2Department of Diagnostic and Biomedical Sciences,
School of Dentistry, The University of Texas Health Science Center at Houston
, Houston, TX, USA
Ransome van der Hoeven
Investigation, Methodology, Resources, Validation, Writing - review & editing
2Department of Diagnostic and Biomedical Sciences,
School of Dentistry, The University of Texas Health Science Center at Houston
, Houston, TX, USA
Hong Liang
Investigation
3Department of Integrative Biology and Pharmacology,
McGovern Medical School, University of Texas Health Science Center
, Houston, TX, USA
Yong Zhou
Data curation, Formal analysis, Investigation, Validation
3Department of Integrative Biology and Pharmacology,
McGovern Medical School, University of Texas Health Science Center
, Houston, TX, USA
Gerald R.V. Hammond
Methodology, Writing - review & editing
4Department of Cell Biology,
University of Pittsburgh School of Medicine
, Pittsburgh, PA, USA
John F. Hancock
Conceptualization, Funding acquisition, Project administration, Writing - review & editing
3Department of Integrative Biology and Pharmacology,
McGovern Medical School, University of Texas Health Science Center
, Houston, TX, USA
Kwang-jin Cho
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1Department of Biochemistry and Molecular Biology,
Boonshoft School of Medicine, Wright State University
, Dayton, OH, USA
Correspondence to Kwang-jin Cho: [email protected]
Disclosures: The authors declare no competing interests exist.
Received:
March 21 2024
Revision Received:
September 08 2024
Accepted:
October 18 2024
Online ISSN: 1540-8140
Print ISSN: 0021-9525
Funding
Funder(s):
Wright State University
Funder(s):
National Cancer Institute
- Award Id(s): R00-CA188593
Funder(s):
National Institute of General Medical Sciences
- Award Id(s): 2R35GM119412
Funder(s):
Cancer Prevention and Research Institute of Texas
- Award Id(s): CPRIT RP200047
© 2025 Lange et al.
2025
Lange et al.
This article is distributed under the terms as described at https://rupress.org/pages/terms102024/.
J Cell Biol (2025) 224 (7): e202403126.
Article history
Received:
March 21 2024
Revision Received:
September 08 2024
Accepted:
October 18 2024
Citation
Taylor E. Lange, Ali Naji, Ransome van der Hoeven, Hong Liang, Yong Zhou, Gerald R.V. Hammond, John F. Hancock, Kwang-jin Cho; MTMR regulates KRAS function by controlling plasma membrane levels of phospholipids. J Cell Biol 7 July 2025; 224 (7): e202403126. doi: https://doi.org/10.1083/jcb.202403126
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